Transfusion Iron Overload

Mohammad Rasel; Sohail Mahboobi

Transfusion Iron Overload

Earn CME/CE in your profession:

Free Review Questions

Continuing Education Activity

Transfusion iron overload is associated with numerous blood transfusions. Excess iron from multiple blood transfusions deposit in different organs throughout the body and causes organ damage. This activity describes the evaluation and management of transfusion iron overload and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

Summarize the etiology of transfusion iron overload.
Identify the most common adverse events associated with transfusion iron overload.
Outline the management options available for transfusion iron overload.
Describe interprofessional team strategies for improving care coordination and communication to enhance the care of patients with transfusion iron overload and improve outcomes.

Introduction

Transfusion iron overload is a major concern in the management of patients with severe anemic syndromes like thalassemia. Because of the close monitoring of iron homeostasis, excess iron from multiple blood transfusions deposits in different organs of the body and causes organ damage. Early iron-chelation therapy can prevent severe life-threatening consequences.

Etiology

Transfusion iron overload is directly associated with the number of blood transfusions. One unit of transfused blood contains about 200-250 mg of iron. In general, patients who receive more than 10 to 20 units of blood are at a significant risk of iron overload.[1] Patients who become transfusion dependent with thalassemia, myelodysplastic syndrome, sickle cell anemia, aplastic anemia, hemolytic anemia, etc. inevitably develop iron overload.

Epidemiology

The incidence of transfusion iron overload varies in different regions of the world, depending on the scope of early screening and preventive measures. Among 925 patients with transfusion-dependent-thalassemia, 36.7% had myocardial iron overload, as documented on cardiac magnetic resonance imaging (MRI) with a myocardial T2* ≤20 milliseconds. Patients in the West and the Far East had a higher iron burden in myocardium compared to the Middle East.[2] In the United States, around 15,000 patients with sickle cell disorder and 4500 patients with myelodysplastic syndromes and other causes of refractory anemias require regular blood transfusions. Internationally, the number reaches about 100,000.[3]

Pathophysiology

There is no effective physiological mechanism for the removal of excess iron from the human body. When a red blood cell (RBC) becomes senescent, the reticuloendothelial macrophage phagocytizes it. Inside the macrophage, the heme part of the RBC breaks down into iron and protoporphyrin. Free iron releases into the plasma. Two molecules of plasma free iron (Fe3+) then bind to one serum transferrin, the main iron transport protein. Transferrin then transports iron to the storage site by binding the transferrin receptor. In iron overload stats, transferrin saturation causes labile plasma iron (LPI) and non-transferrin bound iron (NTBI) to readily enter multiple organs through L-type calcium channels (LCC), ZIP14, and divalent metal transporter (DMT1).[4]

Excess iron in the cytoplasm produces reactive oxygen species via the Fenton and Haber-Weiss reaction. Increased reactive oxygen species levels cause mitochondrial damage, peroxidation of lipids, cell membrane damage, and disruption of the electron transport chain. Over time this leads to apoptosis of the target organ.[5] Recent studies suggest that reactive oxygen species levels also impair the production of nitric oxide and damage the vessel wall.[6] Eventually, chronic iron overload contributes to damage to multiple organs, e.g., cardiomyopathy, cirrhosis of the liver, endocrinopathy, arthritis, etc.

Histopathology

Regular histological stains can not identify iron deposited in the tissue. So, special stain, e.g., Prussian blue stain is commonly used to detect tissue iron overload. A blue granular appearance with Prussian blue stain suggests iron deposition in the tissue. In the hepatocyte, iron deposition begins in the periportal areas. It then progressively involves centrilobular areas, Kupffer cells, and biliary epithelial cells. Over time, iron deposition leads to fibrosis and micronodular cirrhosis. Similarly, iron deposition and fibrosis are seen in cardiac myocytes, the pancreas, endocrine glands, and skin.[7]

History and Physical

Most of the patients with transfusion iron overload typically suffer from the underlying symptoms of anemia (e,g., fatigue, breathlessness, pale skin). The physical presentation of transfusion iron overload varies according to the extent and duration of iron overload. Patients with transfusion iron overload usually present with liver disease (e.g., cirrhosis, hepatic failure), cardiac disease (e.g., dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmia, myocardial infarction, congestive heart failure), endocrinopathy (e.g., diabetes mellitus, hypogonadism, hypothyroidism, hypopituitarism), skin pigmentation, and arthropathy.[8]

Evaluation

A serum ferritin level is an inexpensive and widely available way of assessing transfusion iron overload. A patient with thalassemia with a ferritin measurement of more than 2500 ng/dL has an 80% greater chance of cardiac-related mortality.[9] However, a clinician should consider other causes of raised serum ferritin levels (e.g., an inflammatory disorder, malignancy, metabolic syndrome, renal failure, liver disease, excessive alcohol intake) when assessing a patient.[10] Most guidelines recommend serial serum ferritin and transferrin saturation level every three months for a more accurate assessment of the body iron level.[11]

MRI is the gold standard for long term monitoring of liver and cardiac iron levels. Cardiac T2* MRI has a better prognostic value to predict cardiac risk.[12] Most guidelines recommend assessing cardiac and liver MRI once a year. If the liver iron concentration (LIC) is more than 0.15 mg/g dry weight (DW) or cardiac dysfunction is present, repeat the MRI every six months. If the LIC is normal, MRI can be done less frequently (every two years).

Liver biopsy is the standard of care when MRI is not available. However, patient compliance and risk of bleeding have limited its use.

Most guidelines also recommend baseline testing for free thyroxine (T4), thyroid-stimulating hormone (TSH), calcium, phosphate, 25-OH vitamin D, fasting blood sugar (FBS), echocardiography, bone mass densitometry, and follow-up once a year.[11]

Treatment / Management

Management of transfusion iron overload is based on the duration of transfusion dependence and the severity of the underlying disease. The success of therapy significantly depends on patient adherence. Therefore, the treatment regimen should be adjusted to improve patient compliance.

Prophylactic iron chelation therapy should be initiated before clinically significant iron overload occurs. Phlebotomy is not usually done as most of the patients are already anemic. Traditionally after 15 to 20 units of blood transfusions, an iron-chelating agent is initiated. Deferoxamine and deferasirox are commonly used in the United States.

Deferoxamine is the treatment of choice for transfusion iron overload. It is administered as a continuous intravenous or subcutaneous infusion. In the body, it chelates circulating and tissue iron and eliminates it in urine and bile. In contrast, deferasirox is an orally active iron chelator. After absorption, hepatocyte and other tissues take up deferasirox. Deferasirox chelates tissue iron and eliminates it mainly in bile.[13]

Both deferoxamine and deferasirox monotherapy significantly reduce cardiac and hepatic siderosis.[14][15] An average deferoxamine dose of 51 mg/kg at least five days weekly reduces the LIC level by 6.4 mg/g DW.[16] An average deferasirox dose of 30 mg/kg per day reduces the LIC level by 3.1 to 7.8 mg/g DW.[17] The dose of iron chelating agents is frequently titred based on serum ferritin, liver, and cardiac imaging. The goal is to keep the serum ferritin level less than 1000mcg/L, and the cardiac T2* less than <20 milliseconds, and the LIC less than 3 mg/g DW.[18][19][20] In young children, the dose of deferoxamine should not exceed 25 to 30 mg/kg to minimize adverse effects. Pregnant or breast-feeding patients should avoid chelation therapy.[3]

Differential Diagnosis

Medical conditions that mimic transfusion iron overload include hemochromatosis, cardiomyopathy, acute inflammatory conditions, malignancy, arthritis, diabetes mellitus, human immunodeficiency virus (HIV) infection, hemophagocytic lymphohistiocytosis (HLH), dysmetabolic hyperferritinemia, etc.[21]

Pertinent Studies and Ongoing Trials

Several novel concepts are under investigation that may help in the effective treatment of iron overload and the overall survival of the patient. A randomized controlled trial on a calcium channel blocker (amlodipine) as an adjuvant iron chelator shows a significant decrease in myocardial iron concentration.[22] Several phase 2 studies have shown improved adherence with a film-coated oral tablet compared to a dispersible tablet.[23] Gene therapy is another promising option to reduce the transfusion requirement by improving endogenous erythropoiesis.[24] Janus kinase (JAK2) inhibitor and hepcidin analog are currently being investigated as a treatment option.[25][26]

Toxicity and Adverse Effect Management

Iron chelating agents are usually well tolerated by most of the patients. Most of the side effects are dose-dependent and can be easily avoided by a dose adjustment. Regular tests should be performed to monitor chelation associated toxicity. Stop the current medication and re-evaluate if any complications arise.

The side effects of deferoxamine include pain and erythema at the intramuscular or subcutaneous infusion site, acute onset vision loss, deafness,[27] delayed puberty,[28] skeletal dysplasia,[29] anaphylaxis, abdominal pain, nausea, vomiting, diarrhea, increase risk of certain infections (Yersinia enterocolitica, mucormycosis).[30][31]

The most common side effects of deferasirox are rash, gastrointestinal disturbance, fatal gastrointestinal hemorrhage, renal failure, and hepatic impairment.[16]

The most common side effects of deferiprone are gastrointestinal effects, arthropathy, increased level of hepatic enzymes, hepatic fibrosis, agranulocytosis, and neutropenia.[32][33]

Staging

Staging plays an important role in the long-term follow up of body iron and determining treatment options. The staging system is based on the LIC level on liver biopsy and is classified as mild (< 7 mg/g DW), moderate (7-15 mg/g DW), or severe (>15 mg/g DW).[34]

Prognosis

The prognosis of patients with iron overload depends significantly on early detection and adherence to preventive measures. For example, it takes about 1.5 months to reduce 50% of liver iron concentration, whereas cardiac iron concentration takes about 13 months.[35] Enhancement of quality of life and survival in transfusion iron overload patients has been steadily improved since the introduction of preventive iron chelating therapy (ICT).[36] Still, mortality in transfusion iron overload is three times that of the general population.[37]

Complications

Long term complications of transfusion iron overload are cirrhosis of the liver, hepatic failure, cardiomyopathy, conduction defects, heart failure, diabetes mellitus, hypogonadism, hypothyroidism, and arthropathy. Dilated cardiomyopathy is the most common cause of early death.[37]

Deterrence and Patient Education

Serial monitoring of iron stores can prevent iron overload in patients on chronic transfusion therapy. Serum ferritin levels should be monitored every three months, and a serum iron panel should be done once a year. It is recommended to monitor liver and cardiac iron (either by biopsy or MRI) annually and every 3-6 months in patients with heart failure and intensive chelation therapy.[9] Discussion with the patient and family about the advantages and disadvantages of chelation therapy is important to improve compliance of the patient.[3] Also, patients should be advised to avoid iron-rich food (e.g., red meat, beans, spinach) and also avoid excess vitamin C.

Enhancing Healthcare Team Outcomes

Communication between primary clinicians, hematologists, nurses, and other health care staff is essential for early diagnosis and management of transfusion iron overload. Adherence to follow up and iron-chelation therapy have shown an overall improvement in both morbidity and mortality.[38] The psychological effect of long-term transfusion therapy is common, and early evaluation of depression, anxiety, and other disorders is important. Financial implications for long term therapy should also be considered.

Details

References

[1]

Remacha A, Sanz C, Contreras E, De Heredia CD, Grifols JR, Lozano M, Nuñez GM, Salinas R, Corral M, Villegas A, Spanish Society of Blood Transfusion, Spanish Society of Haematology and Haemotherapy. Guidelines on haemovigilance of post-transfusional iron overload. Blood transfusion = Trasfusione del sangue. 2013 Jan:11(1):128-39. doi: 10.2450/2012.0114-11. Epub 2012 Jul 4 [PubMed PMID: 22790272]

[2]

Aydinok Y, Porter JB, Piga A, Elalfy M, El-Beshlawy A, Kilinç Y, Viprakasit V, Yesilipek A, Habr D, Quebe-Fehling E, Pennell DJ. Prevalence and distribution of iron overload in patients with transfusion-dependent anemias differs across geographic regions: results from the CORDELIA study. European journal of haematology. 2015 Sep:95(3):244-53. doi: 10.1111/ejh.12487. Epub 2015 Jan 8 [PubMed PMID: 25418187]

[3]

Brittenham GM. Iron-chelating therapy for transfusional iron overload. The New England journal of medicine. 2011 Jan 13:364(2):146-56. doi: 10.1056/NEJMct1004810. Epub [PubMed PMID: 21226580]

[4]

Coates TD. Physiology and pathophysiology of iron in hemoglobin-associated diseases. Free radical biology & medicine. 2014 Jul:72():23-40. doi: 10.1016/j.freeradbiomed.2014.03.039. Epub 2014 Apr 12 [PubMed PMID: 24726864]

[5]

Gordan R, Wongjaikam S, Gwathmey JK, Chattipakorn N, Chattipakorn SC, Xie LH. Involvement of cytosolic and mitochondrial iron in iron overload cardiomyopathy: an update. Heart failure reviews. 2018 Sep:23(5):801-816. doi: 10.1007/s10741-018-9700-5. Epub [PubMed PMID: 29675595]

[6]

Marques VB, Nascimento TB, Ribeiro RF Jr, Broseghini-Filho GB, Rossi EM, Graceli JB, dos Santos L. Chronic iron overload in rats increases vascular reactivity by increasing oxidative stress and reducing nitric oxide bioavailability. Life sciences. 2015 Dec 15:143():89-97. doi: 10.1016/j.lfs.2015.10.034. Epub 2015 Oct 30 [PubMed PMID: 26523985]

[7]

Deugnier Y, Turlin B. Pathology of hepatic iron overload. World journal of gastroenterology. 2007 Sep 21:13(35):4755-60 [PubMed PMID: 17729397]

[8]

Goldberg SL, Chen E, Corral M, Guo A, Mody-Patel N, Pecora AL, Laouri M. Incidence and clinical complications of myelodysplastic syndromes among United States Medicare beneficiaries. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010 Jun 10:28(17):2847-52. doi: 10.1200/JCO.2009.25.2395. Epub 2010 Apr 26 [PubMed PMID: 20421543]

[9]

Wood JC. Diagnosis and management of transfusion iron overload: the role of imaging. American journal of hematology. 2007 Dec:82(12 Suppl):1132-5 [PubMed PMID: 17963249]

[10]

Cullis JO, Fitzsimons EJ, Griffiths WJ, Tsochatzis E, Thomas DW, British Society for Haematology. Investigation and management of a raised serum ferritin. British journal of haematology. 2018 May:181(3):331-340. doi: 10.1111/bjh.15166. Epub 2018 Apr 19 [PubMed PMID: 29672840]

[11]

Taher AT, Saliba AN. Iron overload in thalassemia: different organs at different rates. Hematology. American Society of Hematology. Education Program. 2017 Dec 8:2017(1):265-271. doi: 10.1182/asheducation-2017.1.265. Epub [PubMed PMID: 29222265]

[12]

Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce NH, Firmin DN, Wonke B, Porter J, Walker JM, Pennell DJ. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. European heart journal. 2001 Dec:22(23):2171-9 [PubMed PMID: 11913479]

[13]

Waldmeier F, Bruin GJ, Glaenzel U, Hazell K, Sechaud R, Warrington S, Porter JB. Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state. Drug metabolism and disposition: the biological fate of chemicals. 2010 May:38(5):808-16. doi: 10.1124/dmd.109.030833. Epub 2010 Jan 22 [PubMed PMID: 20097723]

[14]

Pennell DJ, Porter JB, Cappellini MD, El-Beshlawy A, Chan LL, Aydinok Y, Elalfy MS, Sutcharitchan P, Li CK, Ibrahim H, Viprakasit V, Kattamis A, Smith G, Habr D, Domokos G, Roubert B, Taher A. Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta-thalassemia. Blood. 2010 Mar 25:115(12):2364-71. doi: 10.1182/blood-2009-04-217455. Epub 2009 Dec 8 [PubMed PMID: 19996412]

[15]

Aydinok Y, Ulger Z, Nart D, Terzi A, Cetiner N, Ellis G, Zimmermann A, Manz C. A randomized controlled 1-year study of daily deferiprone plus twice weekly desferrioxamine compared with daily deferiprone monotherapy in patients with thalassemia major. Haematologica. 2007 Dec:92(12):1599-606 [PubMed PMID: 18055982]

Level 1 (high-level) evidence

[16]

Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L, Aydinok Y, Kattamis A, Kilinc Y, Porter J, Capra M, Galanello R, Fattoum S, Drelichman G, Magnano C, Verissimo M, Athanassiou-Metaxa M, Giardina P, Kourakli-Symeonidis A, Janka-Schaub G, Coates T, Vermylen C, Olivieri N, Thuret I, Opitz H, Ressayre-Djaffer C, Marks P, Alberti D. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. 2006 May 1:107(9):3455-62 [PubMed PMID: 16352812]

[17]

Cappellini MD, Bejaoui M, Agaoglu L, Canatan D, Capra M, Cohen A, Drelichman G, Economou M, Fattoum S, Kattamis A, Kilinc Y, Perrotta S, Piga A, Porter JB, Griffel L, Dong V, Clark J, Aydinok Y. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up. Blood. 2011 Jul 28:118(4):884-93. doi: 10.1182/blood-2010-11-316646. Epub 2011 May 31 [PubMed PMID: 21628399]

[18]

Aydinok Y, Kattamis A, Viprakasit V. Current approach to iron chelation in children. British journal of haematology. 2014 Jun:165(6):745-55. doi: 10.1111/bjh.12825. Epub 2014 Mar 20 [PubMed PMID: 24646011]

[19]

Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood. 1997 Feb 1:89(3):739-61 [PubMed PMID: 9028304]

[20]

Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood. 2011 Sep 29:118(13):3479-88. doi: 10.1182/blood-2010-08-300335. Epub 2011 Aug 2 [PubMed PMID: 21813448]

[21]

Mendler MH, Turlin B, Moirand R, Jouanolle AM, Sapey T, Guyader D, Le Gall JY, Brissot P, David V, Deugnier Y. Insulin resistance-associated hepatic iron overload. Gastroenterology. 1999 Nov:117(5):1155-63 [PubMed PMID: 10535879]

[22]

Khaled A, Salem HA, Ezzat DA, Seif HM, Rabee H. A randomized controlled trial evaluating the effects of amlodipine on myocardial iron deposition in pediatric patients with thalassemia major. Drug design, development and therapy. 2019:13():2427-2436. doi: 10.2147/DDDT.S211630. Epub 2019 Jul 22 [PubMed PMID: 31413542]

Level 1 (high-level) evidence

[23]

Taher AT, Origa R, Perrotta S, Kourakli A, Ruffo GB, Kattamis A, Goh AS, Cortoos A, Huang V, Weill M, Merino Herranz R, Porter JB. New film-coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower-risk MDS: Results of the randomized, phase II ECLIPSE study. American journal of hematology. 2017 May:92(5):420-428. doi: 10.1002/ajh.24668. Epub 2017 Feb 18 [PubMed PMID: 28142202]

Level 1 (high-level) evidence

[24]

Cavazzana M, Antoniani C, Miccio A. Gene Therapy for β-Hemoglobinopathies. Molecular therapy : the journal of the American Society of Gene Therapy. 2017 May 3:25(5):1142-1154. doi: 10.1016/j.ymthe.2017.03.024. Epub 2017 Apr 1 [PubMed PMID: 28377044]

[25]

Motta I, Scaramellini N, Cappellini MD. Investigational drugs in phase I and phase II clinical trials for thalassemia. Expert opinion on investigational drugs. 2017 Jul:26(7):793-802. doi: 10.1080/13543784.2017.1335709. Epub 2017 Jun 5 [PubMed PMID: 28540737]

Level 3 (low-level) evidence

[26]

Preza GC, Ruchala P, Pinon R, Ramos E, Qiao B, Peralta MA, Sharma S, Waring A, Ganz T, Nemeth E. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. The Journal of clinical investigation. 2011 Dec:121(12):4880-8. doi: 10.1172/JCI57693. Epub [PubMed PMID: 22045566]

Level 2 (mid-level) evidence

[27]

Olivieri NF, Buncic JR, Chew E, Gallant T, Harrison RV, Keenan N, Logan W, Mitchell D, Ricci G, Skarf B. Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. The New England journal of medicine. 1986 Apr 3:314(14):869-73 [PubMed PMID: 3485251]

[28]

De Sanctis V, Roos M, Gasser T, Fortini M, Raiola G, Galati MC, Italian Working Group on Endocrine Complications in Non-Endocrine Diseases. Impact of long-term iron chelation therapy on growth and endocrine functions in thalassaemia. Journal of pediatric endocrinology & metabolism : JPEM. 2006 Apr:19(4):471-80 [PubMed PMID: 16759032]

[29]

Chan YL, Pang LM, Chik KW, Cheng JC, Li CK. Patterns of bone diseases in transfusion-dependent homozygous thalassaemia major: predominance of osteoporosis and desferrioxamine-induced bone dysplasia. Pediatric radiology. 2002 Jul:32(7):492-7 [PubMed PMID: 12107582]

[30]

Robins-Browne RM, Prpic JK. Effects of iron and desferrioxamine on infections with Yersinia enterocolitica. Infection and immunity. 1985 Mar:47(3):774-9 [PubMed PMID: 3972453]

[31]

Ammon A, Rumpf KW, Hommerich CP, Behrens-Baumann W, Rüchel R. [Rhinocerebral mucormycosis during deferoxamine therapy]. Deutsche medizinische Wochenschrift (1946). 1992 Sep 18:117(38):1434-8 [PubMed PMID: 1526205]

[32]

Tricta F, Uetrecht J, Galanello R, Connelly J, Rozova A, Spino M, Palmblad J. Deferiprone-induced agranulocytosis: 20 years of clinical observations. American journal of hematology. 2016 Oct:91(10):1026-31. doi: 10.1002/ajh.24479. Epub 2016 Aug 4 [PubMed PMID: 27415835]

[33]

Wu SF, Peng CT, Wu KH, Tsai CH. Liver fibrosis and iron levels during long-term deferiprone treatment of thalassemia major patients. Hemoglobin. 2006:30(2):215-8 [PubMed PMID: 16798646]

[34]

Telfer PT, Prestcott E, Holden S, Walker M, Hoffbrand AV, Wonke B. Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major. British journal of haematology. 2000 Sep:110(4):971-7 [PubMed PMID: 11054091]

[35]

Anderson LJ, Westwood MA, Holden S, Davis B, Prescott E, Wonke B, Porter JB, Walker JM, Pennell DJ. Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospective study using T2* cardiovascular magnetic resonance. British journal of haematology. 2004 Nov:127(3):348-55 [PubMed PMID: 15491298]

[36]

Gabutti V, Piga A. Results of long-term iron-chelating therapy. Acta haematologica. 1996:95(1):26-36 [PubMed PMID: 8604584]

[37]

Fung EB, Harmatz P, Milet M, Ballas SK, De Castro L, Hagar W, Owen W, Olivieri N, Smith-Whitley K, Darbari D, Wang W, Vichinsky E, Multi-Center Study of Iron Overload Research Group. Morbidity and mortality in chronically transfused subjects with thalassemia and sickle cell disease: A report from the multi-center study of iron overload. American journal of hematology. 2007 Apr:82(4):255-65 [PubMed PMID: 17094096]

[38]

Ricchi P, Meloni A, Pistoia L, Spasiano A, Spiga A, Allò M, Gamberini MR, Lisi R, Campisi S, Peluso A, Missere M, Renne S, Mangione M, Positano V, Pepe A. The effect of desferrioxamine chelation versus no therapy in patients with non transfusion-dependent thalassaemia: a multicenter prospective comparison from the MIOT network. Annals of hematology. 2018 Oct:97(10):1925-1932. doi: 10.1007/s00277-018-3397-3. Epub 2018 Jun 21 [PubMed PMID: 29926157]

[39]

Anderson GJ. Mechanisms of iron loading and toxicity. American journal of hematology. 2007 Dec:82(12 Suppl):1128-31 [PubMed PMID: 17963252]

[40]

Munro MG, Mast AE, Powers JM, Kouides PA, O'Brien SH, Richards T, Lavin M, Levy BS. The relationship between heavy menstrual bleeding, iron deficiency, and iron deficiency anemia. American journal of obstetrics and gynecology. 2023 Jul:229(1):1-9. doi: 10.1016/j.ajog.2023.01.017. Epub 2023 Jan 24 [PubMed PMID: 36706856]

[41]

Woei-A-Jin FJSH, Zheng SZ, Kiliçsoy I, Hudig F, Luelmo SAC, Kroep JR, Lamb HJ, Osanto S. Lifetime Transfusion Burden and Transfusion-Related Iron Overload in Adult Survivors of Solid Malignancies. The oncologist. 2020 Feb:25(2):e341-e350. doi: 10.1634/theoncologist.2019-0222. Epub 2019 Aug 27 [PubMed PMID: 32043782]

[42]

Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR, Thalassemia Clinical Research Network. Complications of beta-thalassemia major in North America. Blood. 2004 Jul 1:104(1):34-9 [PubMed PMID: 14988152]